CNS hypoxia is more pronounced in murine cerebral than noncerebral malaria and is reversed by erythropoietin

Hempel, C; Combes, V; Hunt, NH; Kurtzhals, JAL; Grau, GER

CNS hypoxia is more pronounced in murine cerebral than noncerebral malaria and is reversed by erythropoietin

Hempel, C Combes, V

Hunt, NH Kurtzhals, JAL Grau, GER

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Publication Type:: Journal Article
Citation:: American Journal of Pathology, 2011, 179 (4), pp. 1939 - 1950
Issue Date:: 2011-10-01

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Field	Value	Language
dc.contributor.author	Hempel, C	en_US
dc.contributor.author	Combes, V https://orcid.org/0000-0003-2178-3596	en_US
dc.contributor.author	Hunt, NH	en_US
dc.contributor.author	Kurtzhals, JAL	en_US
dc.contributor.author	Grau, GER	en_US
dc.date.available	2011-06-28	en_US
dc.date.issued	2011-10-01	en_US
dc.identifier.citation	American Journal of Pathology, 2011, 179 (4), pp. 1939 - 1950	en_US
dc.identifier.issn	0002-9440	en_US
dc.identifier.uri	http://hdl.handle.net/10453/109930
dc.description.abstract	Cerebral malaria (CM) is associated with high mortality and risk of sequelae, and development of adjunct therapies is hampered by limited knowledge of its pathogenesis. To assess the role of cerebral hypoxia, we used two experimental models of CM, Plasmodium berghei ANKA in CBA and C57BL/6 mice, and two models of malaria without neurologic signs, P. berghei K173 in CBA mice and P. berghei ANKA in BALB/c mice. Hypoxia was demonstrated in brain sections using intravenous pimonidazole and staining with hypoxia-inducible factor-1αspecific antibody. Cytopathic hypoxia was studied using poly (ADP-ribose) polymerase-1 (PARP-1) gene knockout mice. The effect of erythropoietin, an oxygen-sensitive cytokine that mediates protection against CM, on cerebral hypoxia was studied in C57BL/6 mice. Numerous hypoxic foci of neurons and glial cells were observed in mice with CM. Substantially fewer and smaller foci were observed in mice without CM, and hypoxia seemed to be confined to neuronal cell somas. PARP-1deficient mice were not protected against CM, which argues against a role for cytopathic hypoxia. Erythropoietin therapy reversed the development of CM and substantially reduced the degree of neural hypoxia. These findings demonstrate cerebral hypoxia in malaria, strongly associated with cerebral dysfunction and a possible target for adjunctive therapy. © 2011 American Society for Investigative Pathology.	en_US
dc.relation.ispartof	American Journal of Pathology	en_US
dc.relation.isbasedon	10.1016/j.ajpath.2011.06.027	en_US
dc.subject.classification	Pathology	en_US
dc.subject.mesh	Brain	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Plasmodium berghei	en_US
dc.subject.mesh	Parasitemia	en_US
dc.subject.mesh	Malaria, Cerebral	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Erythropoietin	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Fluorescent Dyes	en_US
dc.subject.mesh	Hypoxia	en_US
dc.subject.mesh	Hypoxia-Inducible Factor 1, alpha Subunit	en_US
dc.subject.mesh	Nitroimidazoles	en_US
dc.subject.mesh	Poly(ADP-ribose) Polymerases	en_US
dc.subject.mesh	Survival Analysis	en_US
dc.subject.mesh	Treatment Outcome	en_US
dc.title	CNS hypoxia is more pronounced in murine cerebral than noncerebral malaria and is reversed by erythropoietin	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	179	en_US
utslib.for	0605 Microbiology	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	179	en_US

Abstract:

Cerebral malaria (CM) is associated with high mortality and risk of sequelae, and development of adjunct therapies is hampered by limited knowledge of its pathogenesis. To assess the role of cerebral hypoxia, we used two experimental models of CM, Plasmodium berghei ANKA in CBA and C57BL/6 mice, and two models of malaria without neurologic signs, P. berghei K173 in CBA mice and P. berghei ANKA in BALB/c mice. Hypoxia was demonstrated in brain sections using intravenous pimonidazole and staining with hypoxia-inducible factor-1αspecific antibody. Cytopathic hypoxia was studied using poly (ADP-ribose) polymerase-1 (PARP-1) gene knockout mice. The effect of erythropoietin, an oxygen-sensitive cytokine that mediates protection against CM, on cerebral hypoxia was studied in C57BL/6 mice. Numerous hypoxic foci of neurons and glial cells were observed in mice with CM. Substantially fewer and smaller foci were observed in mice without CM, and hypoxia seemed to be confined to neuronal cell somas. PARP-1deficient mice were not protected against CM, which argues against a role for cytopathic hypoxia. Erythropoietin therapy reversed the development of CM and substantially reduced the degree of neural hypoxia. These findings demonstrate cerebral hypoxia in malaria, strongly associated with cerebral dysfunction and a possible target for adjunctive therapy. © 2011 American Society for Investigative Pathology.

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http://hdl.handle.net/10453/109930